3,7-disubstituted octahydro-2H-pyrido[4,3-E][1,3]oxazin-2-one antibiotics

Abstract

The invention relates to antibacterial compounds of formula I wherein G and K are as defined in the description; and salts of such compounds.

The invention claimed is: 
     
       1. A compound of formula I comprising a relative trans configuration of the octahydro-pyrido[4,3-e][1,3]oxazinone moiety 
       
         
           
           
               
               
           
         
         wherein 
         K represents the group Ka 
       
       
         
           
           
               
               
           
         
         wherein R 1a  represents alkoxy, halogen or cyano; 
         one or two of U a , V a , W a  represent(s) N and the remaining two or one of U a , V a , W a  represent(s) CH; 
         X a  represents CR a  wherein R a  represents hydrogen or halogen; 
         A represents CHR b  wherein R b  represents hydrogen or hydroxyl; 
         or K represents the group Kb 
       
       
         
           
           
               
               
           
         
         wherein R 1b  represents hydrogen, alkoxy, halogen or cyano; 
         one or two of U b , V b  and W b  represent(s) N and the remaining two or one of U b , V b  W b  represent(s) CH; 
         or K represents the group Kc or Kd wherein 
       
       
         
           
           
               
               
           
         
         wherein R 1c  and R 1d  independently represent H or F; 
         V c , V d , W e  and W d  independently represent CH or N; and 
         G represents one of the groups Ga, Gb, Gc and Gd 
       
       
         
           
           
               
               
           
         
         wherein M represents CH or N; and Q and Q′ independently represent O or S; 
       
       or a salt of the compound. 
     
     
       2. The compound according to  claim 1 , wherein K represents the group Ka or Kb; 
       or a salt of the compound. 
     
     
       3. The compound according to  claim 2 , wherein K represents the group Ka wherein R1a represents methoxy, or wherein K represents the group Kb wherein R1b represents methoxy; 
       or a salt of the compound. 
     
     
       4. The compound according to  claim 2 , wherein K represents the group Ka; 
       or a salt of the compound. 
     
     
       5. The compound according to  claim 1 , wherein A represents CHRb wherein Rb represents hydrogen; 
       or a salt of the compound. 
     
     
       6. The compound according to  claim 1 , wherein A represents CHRb wherein Rb represents hydroxyl, and the absolute configuration of the carbon atom to which Rb is attached to is (R); 
       or a salt of the compound. 
     
     
       7. The compound according to  claim 2 , wherein K represents the group Kb; 
       or a salt of the compound. 
     
     
       8. The compound according to  claim 1 , wherein G represents a group of 
       
         
           
           
               
               
           
         
       
       wherein
 M represents CH and Q′ represent O or S; or 
 M represents N and Q′ represents S; and 
 Q represents O or S; 
 
       or a salt of the compound. 
     
     
       9. The compound according to  claim 1 , wherein:
 K represents the group Ka 
 
       
         
           
           
               
               
           
         
         wherein R 1a  represents methoxy; 
         U a  and W a  each represent N and V a  and X a  each represent CH; 
         X a  represents CR a  wherein R a  represents fluorine; 
         A represents CHR b  wherein R b  represents hydrogen or hydroxyl; 
         or K represents the group Kb 
       
       
         
           
           
               
               
           
         
         wherein R 1b  represents methoxy; 
         U b  represents N, V b  represents CH and W b  represents CH or N; and 
         G represents one of the groups Gb and Gc 
       
       
         
           
           
               
               
           
         
         wherein Q represents O or S; 
       
       or a salt of the compound. 
     
     
       10. The compound according to  claim 1 , wherein the compound is:
 (4aR,8aR)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-[2-(3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aS,8aS)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-[2-(3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-[2-hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-7-[2-(3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-[2-(3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxy-ethyl]-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-7-[2-(3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-[2-(7-methoxy-2-oxo-2H-quinolin-1-yl)-ethyl]-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-[2-(7-methoxy-2-oxo-2H-quinoxalin-1-yl)-ethyl]-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-[2-(7-methoxy-2-oxo-2H-[1,8]naphthyridin-1-yl)-ethyl]-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-[2-(6-methoxy-3-oxo-3H-pyrido[2,3-b]pyrazin-4-yl)-ethyl]-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-[2-(3-methoxy-6-oxo-6H-pyrido[2,3-b]pyrazin-5-yl)-ethyl]-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-[(R)-2-(3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxy-ethylkoctahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aS,8aS)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-[(S)-2-(3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxy-ethyl]-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR,8aR)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-[(S)-2-(3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-2-hydroxy-ethyl]-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-[2-(7-fluoro-2-methoxy-quinolin-8-yl)-2-hydroxy-ethyl]-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-[2-(6-fluoro-3-methoxy-quinoxalin-5-yl)-2-hydroxy-ethyl]-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7-[2-hydroxy-2-(3-methoxy-quinoxalin-5-yl)-ethyl]-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-7-[2-(3-fluoro-6-methoxy[1,5]naphthyridn-4-yl)-ethyl]-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR,8aR)-7-[2-(3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b)][1,4]thiazin-6-yl)-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aS,8aS)-7-[2-(3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-3-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-7-[2-(3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-ethylkoctahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-3-(6,7-dihydro-[1,4]dioxino[2,3-c]pyridazin-3-yl)-7-[2-(3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-3-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-7-[2-(3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-7-[2-(7-methoxy-2-oxo-2H-[1,8]naphthyridin-1-yl)-ethyl]-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-7-[2-(7-methoxy-2-oxo-2H-[1,8]naphthyridin-1-yl)-ethyl]-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-3-(6,7-dihydro-8-oxa-5-thia-1,2-diaza-naphthalen-3-yl)-7-[2-(3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-3-(6,7-dihydro-8-oxa-5-thia-1,2-diaza-naphthalen-3-yl)-7-[2-(6-methoxy-3-oxo-3H-pyrido[2,3-b]pyrazin-4-yl)-ethyl]-octahydro-pyrido[4,3-e][1,3]oxazin-2-one; 
 (R)-2-[(4aR*,8aR*)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-oxo-octahydro-pyrido[4,3-e][1,3]oxazin-7-ylmethyl]-9-fluoro-1,2-dihydro-pyrrolo[3,2,1-ij]quinolin-4-one; 
 4-[(4aR*,8aR*)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-oxo-octahydro-pyrido[4,3-e][1,3]oxazin-7-ylmethyl]-3-fluoro-4,5-dihydro-pyrrolo[3,2,1-de][1,5]naphthyridin-7-one; 
 (4aR*,8aR*)-7-(2-(7-methoxy-2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)-3-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)octahydro-2H-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-7-((2RS)-2-(3-fluoro-6-methoxy-1,5-naphthyridin-4-yl)-2-hydroxyethyl)-3-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)octahydro-2H-pyrido[4,3-e][1,3]oxazin-2-one; 
 (4aR*,8aR*)-7-(((R)-9-fluoro-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-2-yl)methyl)-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)octahydro-2H-pyrido[4,3-e][1,3]oxazin-2-one; or 
 (4aR*,8aR*)-7-(2-(7-methoxy-2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)octahydro-2H-pyrido[4,3-e][1,3]oxazin-2-one; 
 
       or a salt of the compound. 
     
     
       11. A pharmaceutical composition comprising as an active principle the compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient. 
     
     
       12. A method of treating a bacterial infection comprising administering to a subject in need thereof an effective amount of the compound according to  claim 1 , wherein the bacterial infection is a respiratory tract infection, otitis media, meningitis, skin and soft tissue infection, pneumonia, bacteremia, endocarditis, intraabdominal infection, gastrointestinal infection,  Clostridium difficile  infection, urinary tract infection, sexually transmitted infection, foreign body infection, osteomyelitis, lyme disease, topical infection, opthalmological infection, tuberculosis, tropical disease or combinations thereof. 
     
     
       13. The method according to  claim 12 , wherein the bacterial infection is respiratory tract infection, otitis media, meningitis, skin and soft tissue infection, pneumonia, bacteremia, or combinations thereof. 
     
     
       14. The method according to  claim 12 , wherein the bacterial infection is caused by  Staphylococcus aureus.    
     
     
       15. A method of treating a bacterial infection caused by  Staphylococcus aureus  bacteria comprising administering to a subject in need thereof an effective amount of the compound according to  claim 1 .